KAsH: A new tool to predict in-hospital mortality in patients with myocardial infarction.

INTRODUCTION: Complex risk scores have limited applicability in the assessment of patients with myocardial infarction (MI). In this work, the authors aimed to develop a simple to use clinical score to stratify the in-hospital mortality risk of patients with MI at first medical contact. METHODS: In this single-center prospective registry assessing 1504 consecutively admitted patients with MI, the strongest predictors of in-hospital mortality were selected through multivariate logistic regression. The KAsH score was developed according to the following formula: KAsH=(Killip class×Age×Heart rate)/systolic blood pressure. Its predictive power was compared to previously validated scores using the DeLong test. The score was categorized and further compared to the Killip classification. RESULTS: The KAsH score displayed excellent predictive power for in-hospital mortality, superior to other well-validated risk scores (AUC: KAsH 0.861 vs. GRACE 0.773, p<0.001) and robust in subgroup analysis. KAsH maintained its predictive capacity after adjustment for multiple confounding factors such as diabetes, heart failure, mechanical complications and bleeding (OR 1.004, 95% CI 1.001-1.008, p=0.012) and reclassified 81.5% of patients into a better risk category compared to the Killip classification. KAsH's categorization displayed excellent mortality discrimination (KAsH 1: 1.0%, KAsH 2: 8.1%, KAsH 3: 20.4%, KAsH 4: 55.2%) and better mortality prediction than the Killip classification (AUC: KAsH 0.839 vs. Killip 0.775, p<0.0001). CONCLUSION: KAsH, an easy to use score calculated at first medical contact with patients with MI, displays better predictive power for in-hospital mortality than existing scores.

Additional value of a combined genetic risk score to standard cardiovascular stratification.

The utility of genetic risk scores (GRS) as independent risk predictors remains inconclusive. Here, we evaluate the additive value of a multi-locus GRS to the Framingham risk score (FRS) in coronary artery disease (CAD) risk prediction. A total of 2888 individuals (1566 coronary patients and 1322 controls) were divided into three subgroups according to FRS. Multiplicative GRS was determined for 32 genetic variants associated to CAD. Logistic Regression and Area Under the Curve (AUC) were determined first, using the TRF for each FRS subgroup, and secondly, adding GRS. Different models (TRF, TRF+GRS) were used to classify the subjects into risk categories for the FRS 10-year predicted risk. The improvement offered by GRS was expressed as Net Reclassification Index and Integrated Discrimination Improvement. Multivariate analysis showed that GRS was an independent predictor for CAD (OR = 1.87; p<0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking status were also independent CAD predictors (p<0.05). GRS added predictive value to TRF across all risk subgroups. NRI showed a significant improvement in all categories. In conclusion, GRS provided a better incremental value in intermediate subgroup. In this subgroup, inclusion of genotyping may be considered to better stratify cardiovascular risk.

[Genetic Polymorphisms Associated with the Onset of Arterial Hypertension in a Portuguese Population]. / Polimorfismos Genéticos Associados ao Aparecimento de Hipertensão Arterial Numa População Portuguesa.

INTRODUCTION: Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors. OBJECTIVE: Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology. MATERIAL AND METHODS: Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0. RESULTS: The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018). DISCUSSION: According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology. CONCLUSION: In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model.

Introdução: A hipertensão arterial é uma doença complexa, multifatorial, controlada por fatores genéticos e ambientais.Objetivo: Avaliar a susceptibilidade genética no aparecimento de hipertensão arterial e sua associação com os fatores de risco tradicionais na eclosão desta patologia.Material e Métodos: Estudo caso-controlo com 1712 indivíduos, idade média de 51,0 ± 7,9 anos (860 hipertensos e 852 controlos). Avaliaram-se os fatores tradicionais, bioquímicos e as variantes genéticas: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. Calculámos o risco de cada gene para a hipertensão, pelos modelos dominante, recessivo, co-dominante e multiplicativo. Através da regressão logística, avaliámos as variáveis associadas à hipertensão. Elaboraram-se curvas ROC com os fatores tradicionais e posteriormente adicionando as variantes genéticas associadas com hipertensão. Analisámos os dados através do SPSS for Windows 19.0 e MedCalc v. 13.3.3.0.Resultados: As variantes genéticas ADD1 G460W, GNB3 C825T, ACE I/D e ACE A2350G associaram-se à hipertensão. A curva ROC com os factores de risco tradicionais e estas variantes mostrou um incremento na capacidade preditiva de hipertensão (p = 0,018).Discussão: Segundo os resultados do nosso estudo as variantes genéticas que após análise univariada se associaram à hipertensão arterial foram a ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961, GNB3 C825T rs5443. As duas primeiras variantes relacionam-se com a hipertensão arterial por interferirem no sistema renina-angiotensina-aldosterona, que tem um importante papel na regulação da pressão arterial. Salienta-se o facto dos genes que codificam os componentes do sistema renina-angiotensinaaldosterona serem candidatos naturais ao desenvolvimento e progressão da hipertensão arterial. Também na nossa população os polimorfismos da alfa-aducina (ADD1 G460W rs4961), associaram-se à hipertensão arterial. Nesta população portuguesa, conhecida por ter elevado consumo de sal, faz sentido que estes polimorfismos, sejam relevantes na gestão do sal e da água e consequentemente, no aparecimento de hipertensão arterial. A variante genética GNB3 C825T rs5443 que interfere na sinalização intracelular também constituiu uma forte candidata à hipertensão arterial. Com a elaboração da curva ROC e cálculo das AUC inicialmente só com os fatores de risco tradicionais e posteriormente adicionando as variantes ADD1 G460W, GNB3 C825T, ACE I/D e ACE A2350G aos fatores de risco tradicionais, verificámos ter havido um incremento no risco preditivo de hipertensão arterial, relativamente ao existente só com os fatores de risco tradicionais, com significado estatístico (p = 0,018). Isto sugere que a hipertensão arterial é uma doença multifatorial, que resulta da interação de fatores ambientais, genéticos e estilos de vida que interagem entre si e levam ao aparecimento desta importante patologia.Conclusão: No nosso estudo os polimorfismos associados à hipertensão, estão ligados ao eixo renina-angiotensina-aldosterona (ACE I/D, ACE A2350G), bem como à gestão de sal e água (ADD1 G460W, GNB3 C825T). Através de uma análise multivariada, concluiu-se que estas duas últimas variantes genéticas conjuntamente com quatro dos fatores tradicionais (tabagismo, hábitos alcoólicos, obesidade e diabetes) se associam de forma significativa e independente à hipertensão arterial essencial. Num modelo preditivo de hipertensão arterial, a introdução das variantes genéticas aumenta ligeiramente o valor preditivo do modelo.

The genetic variant C825T of the beta 3 subunit of G protein is associated with hypertension in a Portuguese population. / A variante genética c825t da subunidade ß3da proteína G associa­se com a hipertensão arterial numa população portuguesa.

INTRODUCTION: Hypertension is an important public health problem, affecting about 25% of the adult population worldwide.1 Genetic and environmental factors contribute to its pathogenesis. The T allele of the C825T polymorphism of the beta 3 subunit of G protein (rs5443) leads to the production of a truncated variant that enhances intracellular signaling and may interfere with the regulation of blood pressure. This genetic variant has been described as a risk factor for hypertension, although study results are controversial. OBJECTIVE: The objective of this study was to analyze the association of the C825T polymorphism of the GNB3 gene with the occurrence of hypertension in a Portuguese population from the Madeira archipelago. METHODS: A case-control study was performed with 1641 Caucasian individuals (mean age 50.6±8.1 years), 848 with hypertension and 793 controls. Blood was collected from all participants for biochemical and genetic analysis, including genotyping of the C825T polymorphism. Logistic regression analysis was performed to determine which variables were significantly associated with the onset of hypertension. Statistical analyses were performed using IBM SPSS version 19.0 and p-values <0.05 were considered statistically significant. RESULTS: In our study, there was a significant association between the C825T polymorphism of the GNB3 gene and the occurrence of hypertension (odds ratio 1.275; 95% confidence interval 1.042-1.559; p=0.018) in the dominant model, after multivariate analysis. CONCLUSION: We conclude that the C825T polymorphism of the beta 3 subunit of G protein is significantly and independently associated with the occurrence of hypertension in the study population.

Relationship between ADD1 Gly460Trp gene polymorphism and essential hypertension in Madeira Island.

Essential hypertension (EH) is a complex disease in which physiological, environmental, and genetic factors are involved in its genesis. The genetic variant of the alpha-adducin gene (ADD1) has been described as a risk factor for EH, but with controversial results.The objective of this study was to evaluate the association of ADD1 (Gly460Trp) gene polymorphism with the EH risk in a population from Madeira Island.A case-control study with 1614 individuals of Caucasian origin was performed, including 817 individuals with EH and 797 controls. Cases and controls were matched for sex and age, by frequency-matching method. All participants collected blood for biochemical and genotypic analysis for the Gly460Trp polymorphism. We further investigated which variables were independently associated to EH, and, consequently, analyzed their interactions.In our study, we found a significant association between the ADD1 gene polymorphism and EH (odds ratio 2.484, P = .01). This association remained statistically significant after the multivariate analysis (odds ratio 2.548, P = .02).The ADD1 Gly460Trp gene polymorphism is significantly and independently associated with EH risk in our population. The knowledge of genetic polymorphisms associated with EH is of paramount importance because it leads to a better understanding of the etiology and pathophysiology of this pathology.

Synergistic Association of Genetic Variants with Environmental Risk Factors in Susceptibility to Essential Hypertension.

AIMS: Essential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development. METHODS: We performed a case-control study with 1641 participants (mean age 50.6 ± 8.1 years), specifically 848 patients with EH and 793 controls, adjusted for gender and age. Traditional risk factors, biochemical and genetic parameters, including the genotypic discrimination of 14 genetic variants previously associated with EH, were investigated. Multifactorial dimensionality reduction (MDR) software was used to analyze gene-environment interactions. Validation was performed using logistic regression analysis with environmental risk factors, significant genetic variants, and the best MDR model. RESULTS: The best model indicates that the interactions among the ADD1 rs4961 640T allele, diabetes, and obesity (body mass index ≥30) increase approximately four-fold the risk of EH (odds ratio = 3.725; 95% confidence interval: 2.945-4.711; p < 0.0001). CONCLUSION: This work showed that the interaction between the ADD1 rs4961 variant, obesity, and the presence of diabetes increased the susceptibility to EH four-fold. In these circumstances, lifestyle adjustment and diabetes control should be intensified in patients who carry the ADD1 variant.

Genetic risk score and cardiovascular mortality in a southern european population with coronary artery disease.

Several genetic risk scores (GRS) have been associated with cardiovascular disease; their role, however, in survival from proven coronary artery disease (CAD) have yielded conflicting results. OBJECTIVE: The objective of this study was to evaluate long-term cardiovascular mortality according to the genetic risk score in a Southern European population with CAD. METHODS: A cohort of 1464 CAD patients with angiographic proven CAD were followed up prospectively for up to 58.3 (interquartile range: 25.8-88.1) months. Genotyping of 32 single-nucleotide polymorphisms previously associated with CAD was performed using oligonucleotides probes marked with fluorescence for each allele. GRS was constructed according to the additive model assuming codominance and categorised using the median (=26). Cox Regression analysis was performed to determine independent multivariate predictors of cardiovascular mortality. Kaplan-Meier survival curves compared high vs low GRS using log-rank test. C-index was done for our population, as a measure of discrimination in survival analysis model. RESULTS: During a mean follow-up of 58.3 months, 156 patients (10.7%) died, 107 (7.3%) of CV causes. High GRS (≥26) was associated with reduced cardiovascular survival. Survival analysis with Cox regression model adjusted for 8 variables showed that high GRS, dyslipidemia, diabetes and 3-vessel disease were independent risk factors for cardiovascular mortality (HR=1.53, P=.037; HR=3.64, P=.012; HR=1.75, P=.004; HR=2.97, P<.0001, respectively). At the end of follow-up, the estimated survival probability was 70.8% for high GRS and 80.8% for low GRS (Log-rank test 5.6; P=.018). C-Index of 0.71 was found when GRS was added to a multivariate survival model of diabetes, dyslipidemia, smoking, hypertension and 3 vessel disease, stable angina and dual antiplatelet therapy. CONCLUSIONS: Besides the classical risk factors management, this work highlights the relevance of the genetic profile in survival from CAD. It is expected that new therapies will be dirsected to gene targets with proven value in cardiovascular survival.

A aquisição da motricidade em crianças portadoras de Síndrome de Down que realizam fisioterapia ou praticam equoterapia / The acquisition of motor skills in children with Down syndrome who perform physical therapy or practice hippotherapy

INTRODUÇÃO: O equilíbrio corporal é um processo complexo envolvendo recepção e integração de estímulos sensoriais integrando as informações provenientes do sistema vestibular, dos receptores visuais e do sistema somatossensorial. OBJETIVO: Verificar a aquisição de marcos motores em crianças portadoras de Síndrome de Down que realizam a equoterapia ou fisioterapia convencional. MATERIAIS E MÉTODOS: Estudo transversal que contou com 33 indivíduos portadores de Síndrome de Down com idade entre 4 e 13 anos, de ambos os sexos, divididos em 2 grupos: Grupo 1 - equoterapia; Grupo 2 - fisioterapia em solo. A motricidade global, o equilíbrio estático e o dinâmico foram avaliados com uso da Escala de Desenvolvimento Motor (EDM). Utilizou-se um questionário para relatar a aquisição de marcos motores, prováveis alterações na acuidade auditiva, visual e/ou posturais, força muscular e o tempo de tratamento. RESULTADOS: Para analise das variáveis, realizou-se o teste de Shapiro--Wilk, o teste de Qui-Quadrado e o teste Exato de Fisher, o teste t e ANOVA seguido de post hoc de Bonferroni; o nível de significância foi 0,05. As aquisições dos marcos motores nas crianças portadoras de Síndrome de Down apresentam atraso considerável em comparação com crianças com desenvolvimento normal p < 0,05. As crianças que realizam fisioterapia apresentam melhor equilíbrio estático e dinâmico do que indivíduos que realizam equoterapia p < 0,05. CONCLUSÃO: A fisioterapia convencional teve influência positiva na obtenção das aquisições motoras e do equilíbrio estático e dinâmico em portadores de Síndrome de Down.

INTRODUCTION: Body balance is a complex process involving reception and integration of sensory stimuli integrating the information from the vestibular system, the visual receptors and the somatosensory system. OBJECTIVE: To investigate the acquisition of motor milestones in children with Down syndrome who perform equine therapy or physical therapy. MATERIALS AND METHODS: Cross-sectional study included 33 individuals with Down syndrome, aged 4 to 13 years, of both sexes divided into two groups: Group 1 - hippotherapy; Group 2 - physiotherapy in soil. Motility global, static and dynamic balance were assessed using the Scale of Motor Development (EDM). We used a questionnaire to report the acquisition of motor milestones, likely changes in hearing acuity, visual and/or postural, muscular strength and treatment time. RESULTS: To examine the variables held the Shapiro-Wilk test, the Chi-Square test and Fisher's exact test, ANOVA followed by Bonferroni post hoc and the significance level was 0.05. The acquisition of motor milestones in children with Down syndrome have considerable delay compared to children with normal development p < 0.05. Children who perform physiotherapy feature both static equilibrium as the dynamic better than individuals performing hippotherapy p < 0.05. CONCLUSION: The conventional physiotherapy had positive influence in getting their motor skills and static and dynamic balance in patients with Down syndrome.

Diabetes e doença cardiovascular: prognóstico após cinco anos de revascularização percutânea / Diabetes and cardiovascular disease: prognosis five years after percutaneous revascularization

Fundamentos: O diabetes mellitus (DM) é reconhecidamente fator de risco cardiovascular. Sabendo-se que a intervenção coronariana percutânea (ICP) melhora o prognóstico da doença coronariana (DC), pretendemos verificar se esse efeito é similar em doentes diabéticos (D) e não diabéticos (ND). Objetivo: Analisar o prognóstico em longo prazo do DM em pacientes submetidos a ICP. Métodos: Estudo de coorte, unicêntrico, retrospectivo, envolvendo pacientes consecutivos submetidos à ICP, eletiva ou de urgência, entre janeiro 2002 e dezembro 2003. Definiram-se dois grupos: pacientes com DM (D) e sem DM (ND). compararam-se as variáveis clínicas e angiográficas da ICP com resultado clínico ao final de cinco anos. Definiram-se como eventos maiores cardiovasculares (EMC): morte, nova síndrome coronariana aguda, acidente vascular encefálico (AVE) e nova revascularização cirúrgica ou ICP. Foram ainda avaliadas as taxas de trombose de stent, revascularização do vaso-alvo (RVA) e revascularização da lesão-alvo (RLA). Resultados: O seguimento em cinco anos foi 94%. Foram realizadas 446 ICP em 406 pacientes, média de idade=63,0+-11 anos, 70,4% masculino. Destes, 128 (31,5%) eram do grupo D. Em cinco anos o valor de EMC foi 50,7% para D e 36,7% para N. Encontrou-se mortalidade global...

Clinical and angiographic profile of the diabetic patient: one-year follow-up.

UNLABELLED: Diabetes mellitus is associated with significant cardiovascular morbidity and mortality. The authors describe the clinical and angiographic profile of a diabetic population undergoing percutaneous coronary intervention, with one-year follow-up. METHODS: We retrospectively studied 769 patients (241 diabetic [D] and 528 nondiabetic [ND]) in terms of clinical and demographic characteristics, angiography and angioplasty data, and medical therapy, and analyzed the composite endpoint of adverse cardiac events at one month and one year. RESULTS: Women, older mean age, hypertension, dyslipidemia, previous stroke and renal insufficiency were more prevalent in the D group. It also had more patients with left ventricular dysfunction, multivessel disease and complex coronary lesions. A significantly higher number of stents per patient and more drug-eluting stents were implanted in this group. Occurrence of the composite endpoint at one-year follow-up was significantly higher in diabetic patients (D = 23.6% vs. ND = 15.9%; p = 0.012), and one-year total mortality was 5.8% in the D group vs. 2.3% in the ND group (p = 0.012). CONCLUSION: Even with aggressive percutaneous and pharmacological management, diabetes mellitus still has an adverse long-term prognosis.

Acute myocardial infarction after thrombolytic treatment of acute ischemic stroke.

Thrombolytic treatment in patients with acute ischemic stroke improves their clinical prognosis when administered within three hours of symptom onset. We report the case of a 57-year-old patient with a history of paroxysmal atrial fibrillation and hypertension who developed an anterior acute myocardial infarction after systemic thrombolytic treatment for acute ischemic stroke. Embolization of a pre-existing cardiac thrombus or in situ formation of a thrombus in a coronary artery has to be considered as a potential adverse effect of thrombolytic therapy in stroke patients.